1. Field of the Invention
The present invention relates to compounds useful in the normalization of a pathologically hyper-excited sensory nerve function in a conscious mammal, particularly a conscious human. In particular, the invention relates to new compounds particularly fused thiophene compounds, methods of synthesis for those compounds, and methods of using those compounds for reducing or eliminating hyper-excited sensory symptoms, such as neuropathic pain.
2. Background
Neuropathic pain is a persistent, chronic pain, generally described as a burning, shooting or lancinating sensation without obvious cause. These symptoms are often associated with damage to the nerves or nerve fibers. Sollevi (U.S. Pat. No. 5,691,318) has described the development of the hyper-excited sensory nerve function that would give rise to neuropathic pain. Generally, this involves some form of trauma, such as infection or mechanical lesion, inflicting damage upon the sensory nervous system.
The sensory nervous system mediates information from peripheral tissues and organs to the brain (CNS). The sensors in these peripheral tissues or organs are sensitive for such qualities as touch, increased or reduced temperature, vibration, pressure, smell, taste, balance, painful stimuli, vision, and hearing, and as such, is important to the subject's physiological control in relation to the surrounding environment. A disturbance of the nerves ability to transmit these sensory signals may lead to reduced sensory perception (hypoestesia) or to hyper-excitation in which there is increased sensory perception (the neuropathic condition). This neuropathic condition may be associated with decreased thresholds for touch and temperature (hyperesthesia), discomfort in the perception of touch or temperature (dysesthesia), discomfort or pain with touch, pressure, and/or thermal stimulation (allodynia), hypersensitivity to pain stimuli (hyperalgesia), balance disturbance, auditory disturbance (tinnitus), or ganglionic dysfunction. The neuropathic condition is generally considered chronic when persistant for 3 months or more.
In recent years, certain treatments for neuropathic pain have been proposed. One such approach has been a certain intrathecal (i.t.) administration of adenosine. When administered via a chronically implanted catheter into the cerebrospinal fluid of mice, Holmgren and coworkers (Naunyn-Schmied. Arch. Pharmacol. 334: 290–293 (1989)) reported a latency to the reflexive paw withdrawal provoked by a hot plate.
In humans with peripheral neuropathic pain, the slow intravenous infusion of adenosine (50–70 micrograms/kg/min) has been reported to alleviate spontaneous pain, relieve tactile allodynia, abolish thermal allodynia, and markedly attenuate hyperalgesia due to pinprick and pressure-induced allodynia. Although the duration of infusion was approximately 40–60 minutes, the effects were reported to last several hours (Sollevi et al, Pain 61: 155–158 (1995); Belfrage et al, Anesth Analg 81: 713–717 (1995); Sollevi, U.S. Pat. No. 5,691,318). In a later study, systemic adenosine administration was shown to reduce the area of dynamic tactile allodynia without significant improvement in spontaneous pain or tactile pain threshold. In some cases, the effect lasted several months (Sjölund et al, Eur. J. Pain 5: 199–207 (2001). Intravenous infusion of adenosine has been shown to reduce secondary hyperalgesia due to cutaneous inflammatory pain in humans (Sjolund et al, Anesth. Analg. 88: 605–610 (1999).
Experimental data indicates that these effects of adenosine are mediated at the spinal level (Salter and Henry, Neuroscience 22: 631–650 (1987)). In a spinal nerve ligation model in rats, intrathecal adenosine produced a dose-dependent reduction in tactile allodynia lasting more than 24 hours (Lavand'homme and Eisenach, Pain 80: 31–36 (1999). These effects were additive with intrathecal morphine and with the α2-adrenergic receptor agonist, clonidine (Gomes et al, Anesthesiology 91: 1072–1079 (1999)). Moreover, the effectiveness of intrathecal adenosine is reversed by the intrathecal administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-diproyplxanthine, but not the adenosine A2-preferential receptor antagonist 3,7-dimethyl-8-propargylxanthine, suggesting the involvement of the adenosine A1 receptor in the mediation of neuropathic pain by adenosine (Gomes et al, Anesthesiology 91: 1072–1079 (1999)). Following intrathecal administration of 500–1000 micrograms of adenosine to humans with chronic neuropathic pain, both spontaneous and evoked pain was reduced in parallel with increased tactile pain thresholds in the allodynic areas and reduced areas of tactile hyperalgesia (Belfrage et al, Anesth. Analg. 89: 136–142 (1999)).
Attempts to modulate the metabolism of adenosine, thereby increasing the endogenous levels have also been examined. In rodents, the use of adenosine deaminase inhibitors to prevent the rapid deamination of adenosine to inosine was shown to greatly enhance the effectiveness of spinal morphine in reducing allodynia. A similar effect was observed with the intrathecal administration of nucleoside transport inhibitors which slow or prevent the cellular uptake of circulating adenosine. Adenosine kinase inhibitors, which prevent the phosphorylation of adenosine to adenosine monophosphate have also been reported as effective (Lynch et al, Eur. J. Pharmacol. 364: 141–146 (1999); Kowaluk et al, J. Pharmacol. Exp. Ther. 295: 1165–1174 (2000); Suzuki et al, Br. J. Pharmacol. 132: 1615–1623 (2001); Zhu et al, Brain Res. 905: 104–110 (2001)). All of these approaches act by increasing the concentration of adenosine available to the adenosine A1 receptor.
Investigations of other modulation of adeonsine receptors have been reported in Bruns et al., Mol. Pharmacol. 38: 939–949 (1990); Bruns et al., Mol. Pharmacol. 38: 950–958 (1990); Bruns et al., Mol. Pharmacol. 38: 939–949, 950–958 (1990), Leung et al, Naunyn-Schmied. Arch. Pharmacol. 352: 206–212 (1995); Baraldi, U.S. Pat. No. 5,939,432; Baraldi et al, Bioorg. Med. Chem. Lett. 10: 1953–1957 (2000); van der Klein et al, J. Med. Chem. 42: 3629–3635 (1999); Kourounakis et al, Drug Dev. Res. 49: 227–237 (2000); and Tranberg et al, J. Med. Chem. 45: 382–389 (2002)).